Insulin resistance (IR) is an obesity-associated disorder representing an important risk factor for non-alcoholic fatty liver diseases (NAFLD) development. The phosphatase PTEN negatively regulates insulin signaling by restraining the PI3K/Akt pathway, a central propagator of insulin signals. Akt is also a key activator of the mammalian target of rapamycin (mTOR), which controls nutrient sensing and regulation of protein/lipid/glucose metabolism. Both PTEN and mTOR expressions/activity are altered with obesity/IR. This thesis project aimed at understanding the PTEN/mTOR-dependent molecular mechanisms contributing to NAFLD development. First, we reported that whereas mTOR inhibition by rapamycin induces weight loss and prevented the development of steatosis in rats, it surprisingly induced a strong skeletal muscles. Second, we established that liver-specific PTEN deletion in mice causes steatosis associated with skeletal muscle insulin hypersensitivity. Together, these studies highlight the key roles of hepatic PTEN and mTOR in the control of the lipid and glucose homeostasis as well as insulin action.